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Gene Section Review

UHMK1 (U2AF homology motif kinase 1) Vanessa Cristina Arfelli, Leticia Fröhlich Archangelo Department of Cellular and Molecular Biology and Pathogenic Bioagents, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, Brazil. [email protected]

Published in Atlas Database: November 2017 Online updated version : http://AtlasGeneticsOncology.org/Genes/UHMK1ID41071ch1q23.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68931/11-2017-UHMK1ID41071ch1q23.pdf DOI: 10.4267/2042/68931 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2018 Atlas of Genetics and Cytogenetics in Oncology and Haematology Abstract Location () Starts at 162497174 and ends at 162529629 bp from UHMK1 (also known as KIS) is a serine/threonine pter (according to GRCh38.p7, 2016) kinase initially identified as a interacting . UHMK1 is characterized by an N-terminal DNA/RNA kinase domain and a C-terminal UHM motif. Through the UHM motif, the protein is capable of Description interacting with splicing factors, such as SF1 and The UHMK1 is located on the 1, SF3B1, involved in early steps of spliceosome band q23, orientated in the plus (+) strand. The assembly. UHMK1 is ubiquitously but genomic locus spans 32456 base pairs preferentially expressed in the developing nervous (NC_000001.11), contains 8 exons and two system, where it plays a role in mRNA processing, alternative first exons. translational enhancing, neurite outgrowth and postsynaptic plasticity. Protein interactions between Transcription UHMK1 and a range of pointed to its Three alternatively spliced transcripts of 8535, 8194 function in different cellular processes, such as RNA and 8446 base pairs are formed (NM_175866, metabolism, cell cycle progression, cell migration NM_001184763 and NM_144624, respectively). and membrane trafficking. More recently, a role of The transcript variant 1 (NM_175866) codes for the UHMK1 in cell differentiation has also been longest protein isoform, which has 419 amino acids proposed. in length (isoform 1; NP_787062). The transcript Keywords variant 2 (NM_001184763) differs in the 5' UTR and phosphorylation; splicing; cell-cycle control; initiates translation at the alternative start codon. The nervous system resulting protein (isoform 2; NP_0011716921) of 345 amino acids has a distinct 15 amino acids N- Identity terminal, encoded by the alternative exon 1, and the remaining 330 amino acids encoded by exons 2-8. Other names The transcript variant 3 (NM_144624) lacks exon 7, KIS, KIST, P-CIP2 which results in a frame shift and early stop codon HGNC (Hugo) within exon 8. The encoded protein (isoform 3; UHMK1 NP_653225) of 344 residues, shares the first 341 Location amino acids (exons 1-6) with isoform 1, differing 1q23.3 only in the last 3 amino acids at the C-terminal

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(Figure 1). An additional processed transcript of UHMK1 locus (NC_000001.11) are shared with the 3345 bp (ENST00000282169.8) retaining intron 2 LOC105371497 gene, which produces a 708 bp long (between exons 2 and 3), which does not contain an non-coding RNA (XR_922225.1), transcribed in the open reading frame (ORF) has been annotated for opposite direction of UHMK1 this gene. Moreover, the first 540 nucleotides of (https://www.ncbi.nlm.nih.gov/gene/127933).

Figure 1. Genomic organization, alternative splicing and protein isoforms of UHMK1. Exons are represented by numbered blue boxes and introns by the black line. The positions of the exons within the genome (NC_000001.11) are numbered. Exon joining is represented for each transcript by light green, purple and orange continuous lines; dashed lines indicate the respective protein isoform; dotted lines indicate the alternatively first exon usage. Size of the transcript variants are shown in parentheses. The transcript variant 1 codes for the longer protein (UHMK1 isoform 1, light green). The transcript variant 2 comprises an alternative first exon (light purple box), which encodes the distinct 15 amino acids N-terminal of the protein (UHMK1 isoform 2, purple). The transcript variant 3 lacks exon 7, whose excision results in a frameshift and early stop codon in exon 8. The resulting UHMK1 isoform 3 (orange), exhibits a distinct C-terminal formed by 3 aminoacids encoded by the beginning of exon 8. Sizes were scaled up, where 0.5 cm symbolizes 150 bp of exonic region (blue boxes) and 624 bp of intronic regions (black line). Number and position of aminoacids are depicted for each isoform.

Protein

Figure 2. Diagram representing UHMK1 protein and the posttranslational modifications. UHMK1 is characterized by an N-terminal kinase core of 282 aminoacids, represented in green and a C-terminal UHM of 100 aminoacids, represented in violet. All residues described to be phosphorylated or ubiquitinated in large scale proteomic studies are depicted. Source: Phosphoproteomic databases PhosphoSitePlus (http://www.phosphosite.org) UHM: U2AF homology motif (modified from Archangelo, et al. 2013).

Description (Kielkopf et al., 2004; Manceau et al., 2006). UHMK1 phosphorylates preferentially proline UHMK1 is a serine/threonine kinase with calculated directed serine residues on its target proteins molecular weight of 46.5 kDa and a theoretical pI of (Maucuer et al., 2000). The lysine 54 within the N- 5.59 (PhosphoSite Plus). The primary sequence of terminal region is essential for its kinase activity and the protein is characterized by an N-terminal kinase autophosphorylation activity has been observed core (282 aminoacids) and the C-terminal U2AF (Boehm et al., 2002; Maucuer et al., 1997). A variety homology motif (UHM), responsible for establishing of large scale proteomic studies identified two types protein interactions with UHM-ligand motifs of posttranslational modifications within UHMK1, (ULM), particularly present among splicing factors

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namely lysine-ubiquitination (K190-ub, K282-ub, to proliferate upon mitogen activation (Barbutti et K383-ub and K387-ub) and phosphorylation (Y197- al., 2017). Moreover, the amount of UHMK1 protein p, S283-p and S290-p) as indicated at the varies throughout the cell cycle. In synchronized phosphoproteomic database PhosphoSitePlus cells, UHMK1 accumulates in G1 phase and (http://www.phosphosite.org) (Figure 2). decreases during S phase of the cell cycle Expression (Archangelo et al., 2013). Little is known about the transcriptional regulation UHMK1 is ubiquitously expressed throughout rat of UHMK1, which was described as direct target of and human tissues, with enriched expression in the the transcription factors GABP (Crook et al., 2008) nervous system (Bieche et al., 2003; Caldwell et al., and FOXM1 (Petrovic et al., 2008). The core 1999; Maucuer et al., 1997). Uhmk1 mRNA is promoter region of UHMK1 was described within - expressed during rat embryonic development and 141 to -41 base pairs upstream of the transcription increases after birth and during the first month of start site and has no consensus sequences for TATA brain development (Bieche et al., 2003). In the adult or CCAAT boxes. Instead, it has GC-box and 3 Ets- brain, in situ hybridization revealed remarkable binding sites (EBS-1, EBS-2 and EBS-3), which are expression in the substantia nigra and some sensorial essential for the promoter activity, in vitro. The and motor nuclei in the brain stem (Bieche et al., regions spanning EBS-1 and EBS-2 (-103/-73 bp), 2003). In the human brain, UHMK1 expression was and EBS-3 (-52/-42 bp) bind GABP in response to detected in all regions examined, with highest levels serum, leading to UHMK1 expression, cell in the deeper cortical layers. Strong expression was migration and cell cycle progression of VSCM cells observed in dentate gyrus, CA1, CA3 and CA4 (Crook et al., 2008). regions of the hippocampus, in Purkinje cells and FoxM1 binds an internal regulatory region within granule cell layer of the cerebellum. No expression UHMK1 and transactivates its expression in vitro. was detected in the white matter (Bristow et al., FoxM1 appears to be essential for serum-dependent 2009). activation of UHMK1 mRNA expression, as In the hematopoietic compartment, high levels of assessed in FoxM1-/- MEF cells. It was suggested UHMK1 transcripts were observed in differentiated that FoxM1-induced UHMK1 expression is required lymphocytes (CD4+, CD8+ and CD19+) compared for UHMK1-mediated phosphorylation and to the progenitor enriched subpopulation (CD34+) or consequently degradation of CDKN1B (p27Kip1) leukemia cell lines. UHMK1 expression was (Petrovic et al., 2008). upregulated in megakaryocytic-, monocytic- and Furthermore, UHMK1 was described as granulocytic-induced differentiation of leukemia cell transcriptional target of the WD repeat domain 5 lines and in erythrocytic-induced differentiation of (WDR5), a core component of the KMT2A (MLL) / primary CD34+ cells (Barbutti et al., 2017). SETD1A complex, known for its methyltransferase Levels of UHMK1 protein are induced by mitogens. activity on H3 lysine 4 (H3K4). The H3K4me3 In serum starved cells, UHMK1 expression was epigenetic modification correlates with gene reduced in contrast to serum stimulated cells (Boehm activation, thus it is suggested that WDR5-mediated et al., 2002; Crook et al., 2008; Petrovic et al., 2008). H3K4me3 at UHMK1 locus promotes its expression UHMK1 expression increased after quiescent (Chen et al., 2015). peripheral blood lymphocytes (PBLs) were induced

Figure 3. Subcellular localization of Uhmk1. Confocal image of HeLa cells transiently transfected with plasmid expressing ha-tagged Uhmk1 (pECE-HA-Kis; Manceau et al, 2008). Ectopic Uhmk1 localizes mainly to the nucleus and to a lesser extent to the cytoplasm. The anti-Kis 3B12 antibody (Manceau et al, 2012) and Phalloidin (Invitrogen A1238) were used to detected Uhmk1 and Actin, respectively. 63x objective, zoom 2,5 x. Personal data.

Localisation 2002; Maucuer et al., 1997) (Figure 3). Shuttling between nucleus and cytoplasm has been described The UHMK1 protein localizes mainly to the nucleus for the GFP-fused protein by fluorescence recovery and to a lesser extent to the cytoplasm (Boehm et al., after photobleaching (FRAP) (Francone et al., 2010).

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The kinase domain is essential for the protein nuclear of cortical neurons (Cambray et al., 2009). Also, a localization, since deletion mutants of this domain, nucleolar enriched localization was observed when particularly the residues 1-211, extinguished Uhmk1 ha-tagged Uhmk1 was co-expressed with its GFP- signal in immunofluorescence analysis (Manceau et fused interacting partner PIMREG (Archangelo et al., 2008). Overexpressed ha-tagged Uhmk1 al., 2013). localized to the RNA granules of axon and dendrites

Figure 4. Potential functions of UHMK1. 1- UHMK1 interacts with and phosphorylates the splicing factors SF1 and SF3B1. 2- UHMK1 counteracts the inhibitory effect of p27Kip1 on cell cycle. Upon mitogenic activation, UHMK1 is upregulated and phosphorylates p27Kip1, which is exported from the nucleus and targeted for degradation by the proteasome. 3- UHMK1 impairs cell migration through negatively regulating the microtubule destabilizing protein Stathmin (STMN). UHMK1-mediated phosphorylation of STMN on S38 targets the protein for degradation. 4- UHMK1 regulates the secretory pathway in neurons and endocrine cells through its interaction with the peptidylglycine α-amidating mono-oxigenase (PAM). 5- UHMK1 interacts with components of neuronal RNA granules, such as KIF3A, NonO and eEF1A. It also associates with RNP-transported mRNAs and stimulates translation driven by the β-actin 3' UTR. 6- UHMK1 interacts with and phosphorylates the proliferation marker PIMREG, suggesting a potential role in regulating proliferation. Black arrow: represents the mitogen-dependent activation of UHMK1. Grey arrows: indicate the UHMK1-mediated phosphorylation of target proteins. Grey dotted arrows: represent the fate of the UHMK1 phosphorylated proteins targeted for degradation. P: phosphorylation; Ub: ubiquitination. Illustration was drawn using Servier Medical Art.

Function expression is necessary for normal phosphorylation of SF1 in vivo (Manceau et al., 2012). The fact that UHMK1 was described to interact with a range of UHMK1 interacts with and regulates splicing factors proteins, shedding light on different functions of this suggests that UHMK1 might be involved in RNA protein in diverse cellular processes (Figure 4). metabolism. UHMK1 is the only kinase that possesses the N- Since UHMK1 is highly expressed in neurons, it is terminal kinase core juxtaposed to a C-terminal expected to exerts important functions in the nervous U2AF homology motif (UHM) (Maucuer et al., system. It was demonstrated an abnormal 1997). Through the UHM motif, UHMK1 interacts phosphorylation of SF1 in brain extracts of neonate with the splicing factors SF1 and SF3B1 (Manceau Uhmk1-/- mice. Also, Uhmk1 deletion resulted in et al., 2008). Upon interaction, UHMK1 increased ratio of pre-mRNA relative to mRNA, and phosphorylates SF1, which enhances SF1 specific consequently down-regulation of brain specific binding to U2AF65 and reduces the SF1-U2AF65 , like cys-loop ligand-gated ion channels and binding to the 3' splice site RNA (Chatrikhi et al., metabolic enzymes. Although adult Uhmk1-/- mice 2016; Manceau et al., 2006). In addition, UHMK1 did not present an obvious phenotype, animal

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behavior was affected. The Uhmk1-/- mice displayed An extensively documented function of UHMK1 is locomotor hyperactivity, reduced fear conditioning its ability to positively regulate cell cycle and learning capacities from aversive stimuli progression through phosphorylation and inhibition (Manceau et al., 2012). of the cyclin dependent kinase inhibitor (CDKI) The murine Uhmk1 was described to interact with p27Kip1. Upon mitogenic activation, UHMK1 known components of neuronal RNA granules, such expression is upregulated and phosphorylates p27Kip1 as KIF3A, NONO and EEF1A1. The protein on serine 10 (Ser10). As a consequence, p27Kip1 is colocalizes with KIF3A kinesin in neurites and is exported from nucleus to cytoplasm, where it is required for neuritic outgrowth in cortical mouse targeted to the proteasome and degraded, and has no neurons. Furthermore, Uhmk1 associates with RNP- longer inhibitory effect on cell cycle. Thus, UHMK1 transported mRNAs and stimulate translation driven promotes cell cycle re-entry by inactivating p27Kip1 by the β-actin 3' UTR, suggesting that Uhmk1 following growth factor stimulation (Boehm et al., contributes to modulate translation in RNA- 2002). transporting granules as a result of local signals Another important target of UHMK1 is the (Cambray et al., 2009). Still, comparison of primary microtubule-destabilizing protein, Stathmin cultures derived from Uhmk1-/- mice did not reveal a (Maucuer et al., 1995). UHMK1 interacts with and significant difference in neuritic arborization of phosphorylates Stathmin on serine 38 (Ser38), cortical neurons (Manceau et al., 2012). targeting this protein to proteasome. Through Furthermore, a study investigating Uhmk1 action on negative regulation of Stathmin, UHMK1 alter hippocampal synaptic plasticity in mice, showed that microtubule dynamics and consequently impairs cell Uhmk1 knockdown impaired spine development, migration (Langenickel et al., 2008). altered actin dynamics, and reduced postsynaptic UHMK1 expression is upregulated upon responsiveness. Moreover, Uhmk1 depletion hematopoietic cell differentiation, thus a possible resulted in decrease of the postsynaptic scaffolding role of UHMK1 in cell differentiation was proposed protein PSD-95 and of AMPA receptor subunits. (Barbutti et al., 2017). This idea was supported by Thus Uhmk1 enhances translation of AMPA the fact that UHMK1 mRNA is highly expressed in receptors and stimulates dendritic spine remodeling the mature brain and in terminally differentiated (Pedraza et al., 2014). neural cells (Bieche et al., 2003) as well as during Another described function of UHMK1 involves the osteoclasts differentiation (Choi et al., 2016). The regulation of secretory pathway in neurons and human UHMK1 shares high homology with a endocrine cells through its interaction with number of species as depicted in Table 1. peptidylglycine α-amidating mono-oxigenase PIMREG (previously known as FAM64A; CATS) is (PAM) (Alam et al., 1996). PAM cytosolic domain a proliferation marker shown to interact with (CD) phosphorylation by UHMK1 (Ser-949) is UHMK1. The fact that UHMK1 interacts with and required for the correct routing of this protein and phosphorylates PIMREG suggests that UHMK1 consequently for its ability to affect trafficking in the regulates PIMREG function and/or localization. regulated secretion pathway (Alam et al., 2001; Nevertheless, the functional implication of this Caldwell et al., 1999). Lately, it was described an interaction remains elusive (Archangelo et al., intramembrane proteolysis pathway for PAM, 2013). generating a soluble fragment of the cytosolic Homology domain (sf-CD), which accumulates in the nucleus in a phosphorylation-dependent manner, modulating The human UHMK1 shares high homology with a the expression of genes involved in the secretory number of species as depicted in Table 1. The human pathway. UHMK1 phosphorylates sf-CD, UHMK1 shares high homology with a number of diminishing its localization in the nucleus and species as depicted in Table 1. negatively regulating the expression of a subset of genes (Francone et al., 2010; Rajagopal et al., 2010). Table 1. Homology between the human UHMK1 and other species

Homo sapiens UHMK1 Symbol Protein (% Identity) DNA(% Identity)

vs. P. troglodytes UHMK1 99.8 (XP_001174268) 99.7 (XM_001174268) vs. M. mulatta UHMK1 99.8 (NP_001253697) 99.0 (NM_001266768)

vs. C. lupus UHMK1 99.8 (XP_536143) 95.8 (XM_536143)

vs. B. taurus UHMK1 99.8 (NP_001192514) 95.9 (NM_001205585)

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vs. M. musculus Uhmk1 99.3 (NP_034763) 93.0 (NM_010633)

vs. R. norvegicus Uhmk1 99.3 (NP_058989) 92.6 (NM_017293)

vs. G. gallus UHMK1 88.2 (XP_015145890) 81.6 (XM_015290404)

vs. D. rerio uhmk1 73.6 (NP_001070127) 69.4 (NM_001076659)

(Source: http://www.ncbi.nlm.nih.gov/homologene/) levels of UHMK1 expression positively impacted Mutations event free and overall survival (Barbutti et al., 2017). Somatic Recurrent mutations have not been identified for the Puri and colleagues performed a fine mapping by UHMK1 gene. Nonetheless, more than 160 unique genetic association and identified two SNPs within mutations were reported in this gene in the catalogue the UHMK1 gene (rs10494370, p =.004, and of somatic mutations in cancer database (COSMIC), rs7513662, p = .043), which showed significant mainly in lung, gastric, esophageal, colon, rectal and association with schizophrenia (Puri et al., 2007). hepatocellular/liver cancer The genetic association of these markers was (http://cancer.sanger.ac.uk/cancergenome/projects/c confirmed in a second case-control (Puri et al., osmic). 2008). Nevertheless, the association of UHMK1 with schizophrenia is controversial since the data Implicated in from different cohorts did not support the findings (Betcheva et al., 2009; Dumaine et al., 2011). Breast cancer Osteoporosis Erlotinib resistence in breast cancer treatment was attributed to p27Kip1 cytoplasmic localization. The SNP rs16863247 was identified within the UHMK1 depletion by siRNA enhanced erlotinib UHMK1 locus in a genome-wide association study cytotoxicity in EGFR-expressing breast cancer cells, (GWAS) carried out to identify genetic variants that due to its accumulation in the nucleus and reduced influence bone mineral density (BMD) in east p27Kip1 cytoplasmic localization (Zhang et al., 2010). Asians. Thus, UHMK1 was described as a bone Besides, UHMK1 expression was reported to be mineral density susceptibility gene for this ethnical inhibited in a dose-dependent manner by the anti- group. The authors also showed opposed expression HER2 antibody trastuzumab, used for treatment of levels of UHMK1 during osteoblast and osteoclast human metastatic breast cancer with HER2 differentiation and proposed that UHMK1 may play overexpression (Le et al., 2005). a role in bone metabolism by controlling osteoclast and osteoblast differentiation (Choi et al., 2016). Neurological tumors Vascular remodeling and wound Higher levels of UHMK1 transcripts were observed in small cohort of neurological tumors associated repair with neurofibromatosis type 1 (NF1). Among the Langenickel and coworkers demonstrated the NF1-associated tumors analyzed, plexiform importance of UHMK1 expression in controlling neurofibroma and malignant peripheral nerve sheath vascular remodeling and wound repair. These tumors (MPNSTs) presented higher UHMK1 processes are characterized by vascular smooth mRNA levels compared to dermal neurofibroma muscle cell (VSCM) proliferation and cell (Bieche et al., 2003). migration, which can be achieved by inhibiting Kip1 Bladder cancer p27 and Stathmin, two known substrates of UHMK1. In a mouse model, deletion of Uhmk1 led Silencing of WDR5, a protein shown to be to accelerated neointima formation and vessel upregulated in bladder cancer, reduced the occlusion, caused by increased migratory activity of H3K4me3 epigenetic marker on its target genes, VSMCs, as a consequence of diminished such as UHMK1 and consequently downregulated degradation of Stathmin (Langenickel et al., 2008). UHMK1 expression in bladder cancer cells (Chen et al., 2015). Corneal fibrosis Hematological malignancies It was shown that FGF2-mediated proliferation of corneal endothelial cells (CECs) is partially No aberrant expression was observed in patient dependent on UHMK1 upregulation and its samples with myelodysplastic syndrome (MDS), inhibitory effects on CDK inhibitor p27Kip1 (Lee and acute myeloid (AML) or lymphoblastic (ALL) Kay, 2011; Lee et al., 2011). leukemia. Nonetheless, in MDS patients, increased

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Cerebral visual impairment amidating monooxygenase cytosolic interactor protein 2 interacts with the cytosolic routing determinants of the UHMK1 was recently reported among candidate peptide processing enzyme peptidylglycine alpha-amidating genes for cerebral visual impairment (CVI), a major monooxygenase J Biol Chem 1999 Dec 3;274(49):34646- cause of low vision in childhood (Bosch et al., 2016). 56 Cambray S, Pedraza N, Rafel M, Garí E, Aldea M, Gallego C. Protein kinase KIS localizes to RNA granules and To be noted enhances local translation Mol Cell Biol 2009 It is well accepted that UHMK1 promotes cell cycle Feb;29(3):726-35 re-entry by inactivating p27Kip1 following growth Chatrikhi R, Wang W, Gupta A, Loerch S, Maucuer A, factor stimulation. Thus it is expected that Kielkopf CL. SF1 Phosphorylation Enhances Specific Binding to U2AF(65) and Reduces Binding to 3'-Splice-Site abnormally elevated UHMK1 activity, which is RNA Biophys J 2016 Dec 20;111(12):2570-2586 supposed to relieve cells from p27Kip-dependent growth inhibition, could be involved in some aspects Chen X, Xie W, Gu P, Cai Q, Wang B, Xie Y, Dong W, He W, Zhong G, Lin T, Huang J. Upregulated WDR5 promotes of tumor development. Nonetheless, no aberrant proliferation, self-renewal and chemoresistance in bladder expression of UHMK1 has been reported amongst cancer via mediating H3K4 trimethylation Sci Rep 2015 Feb different cancer samples (Barbutti et al., 2017; 6;5:8293 Bieche et al., 2003), except in a few cases of Choi HJ, Park H, Zhang L, Kim JH, Kim YA, Yang JY, Pei neurological tumors associated with NF1 (Bieche et YF, Tian Q, Shen H, Hwang JY, Deng HW, Cho NH, Shin al., 2003). Hence, whether it plays a role in CS. Genome-wide association study in East Asians tumorigenesis or not remains largely elusive and suggests UHMK1 as a novel bone mineral density susceptibility gene Bone 2016 Oct;91:113-21 must be further investigated. Crook MF, Olive M, Xue HH, Langenickel TH, Boehm M, Leonard WJ, Nabel EG. GA-binding protein regulates KIS References , cell migration, and cell cycle progression Alam MR, Steveson TC, Johnson RC, Bäck N, Abraham B, FASEB J 2008 Jan;22(1):225-35 Mains RE, Eipper BA. Signaling mediated by the cytosolic Dumaine A, Maucuer A, Barbet A, Manceau V, Deshommes domain of peptidylglycine alpha-amidating J, Méary A, Szöke A, Schürhoff F, Llorca PM, Lancon C, monooxygenase. Mol Biol Cell. 2001 Mar;12(3):629-44 Leboyer M, Jamain S. Genetic and molecular exploration of Archangelo LF, Greif PA, Maucuer A, Manceau V, Koneru UHMK1 in schizophrenic patients Psychiatr Genet 2011 N, Bigarella CL, Niemann F, dos Santos MT, Kobarg J, Dec;21(6):315-8 Bohlander SK, Saad ST. The CATS (FAM64A) protein is a Francone VP, Ifrim MF, Rajagopal C, Leddy CJ, Wang Y, substrate of the Kinase Interacting Stathmin (KIS). Biochim Carson JH, Mains RE, Eipper BA. Signaling from the Biophys Acta. 2013 May;1833(5):1269-79 secretory granule to the nucleus: Uhmk1 and PAM Mol Barbutti I, Machado-Neto J, Arfelli V, Campos P, Traina F, Endocrinol 2010 Aug;24(8):1543-58 Saad S, and Archangelo L.. The U2AF homology motif Kielkopf CL, Lücke S, Green MR. U2AF homology motifs: kinase 1 (UHMK1) is upregulated upon hematopoietic cell protein recognition in the RRM world Genes Dev 2004 Jul differentiation. 2017. DOI: 10.1101/187385. 1;18(13):1513-26 Betcheva ET, Mushiroda T, Takahashi A, Kubo M, Langenickel TH, Olive M, Boehm M, San H, Crook MF, Karachanak SK, Zaharieva IT, Vazharova RV, Dimova II, Nabel EG. KIS protects against adverse vascular Milanova VK, Tolev T, Kirov G, Owen MJ, O'Donovan MC, remodeling by opposing stathmin-mediated VSMC Kamatani N, Nakamura Y, Toncheva DI. Case-control migration in mice J Clin Invest 2008 Dec;118(12):3848-59 association study of 59 candidate genes reveals the DRD2 SNP rs6277 (C957T) as the only susceptibility factor for Le XF, Pruefer F, Bast RC Jr. HER2-targeting antibodies schizophrenia in the Bulgarian population J Hum Genet modulate the cyclin-dependent kinase inhibitor p27Kip1 via 2009 Feb;54(2):98-107 multiple signaling pathways Cell Cycle 2005 Jan;4(1):87- 95 Bièche I, Manceau V, Curmi PA, Laurendeau I, Lachkar S, Leroy K, Vidaud D, Sobel A, Maucuer A. Quantitative RT- Lee JG, Kay EP. PI 3-kinase/Rac1 and ERK1/2 regulate PCR reveals a ubiquitous but preferentially neural FGF-2-mediated cell proliferation through phosphorylation expression of the KIS gene in rat and human Brain Res Mol of p27 at Ser10 by KIS and at Thr187 by Cdc25A/Cdk2 Brain Res 2003 May 26;114(1):55-64 Invest Ophthalmol Vis Sci 2011 Jan 21;52(1):417-26 Boehm M, Yoshimoto T, Crook MF, Nallamshetty S, True A, Lee JG, Song JS, Smith RE, Kay EP. Human corneal Nabel GJ, Nabel EG. A growth factor-dependent nuclear endothelial cells employ phosphorylation of p27(Kip1) at kinase phosphorylates p27(Kip1) and regulates cell cycle both Ser10 and Thr187 sites for FGF-2-mediated cell progression EMBO J 2002 Jul 1;21(13):3390-401 proliferation via PI 3-kinase Invest Ophthalmol Vis Sci 2011 Oct 17;52(11):8216-23 Bosch DG, Boonstra FN, de Leeuw N, Pfundt R, Nillesen WM, de Ligt J, Gilissen C, Jhangiani S, Lupski JR, Cremers Manceau V, Kremmer E, Nabel EG, Maucuer A. The protein FP, de Vries BB. Novel genetic causes for cerebral visual kinase KIS impacts gene expression during development impairment Eur J Hum Genet 2016 May;24(5):660-5 and fear conditioning in adult mice PLoS One 2012;7(8):e43946 Bristow GC, Lane TA, Walker M, Chen L, Sei Y, Hyde TM, Kleinman JE, Harrison PJ, Eastwood SL. Expression of Manceau V, Swenson M, Le Caer JP, Sobel A, Kielkopf CL, kinase interacting with stathmin (KIS, UHMK1) in human Maucuer A. Major phosphorylation of SF1 on adjacent Ser- brain and lymphoblasts: Effects of schizophrenia and Pro motifs enhances interaction with U2AF65 FEBS J 2006 genotype Brain Res 2009 Dec 8;1301:197-206 Feb;273(3):577-87 Caldwell BD, Darlington DN, Penzes P, Johnson RC, Eipper BA, Mains RE. The novel kinase peptidylglycine alpha-

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Maucuer A, Camonis JH, Sobel A. Stathmin interaction with A, Curtis D, St Clair D, Gurling H. Confirmation of the a putative kinase and coiled-coil-forming protein domains genetic association between the U2AF homology motif Proc Natl Acad Sci U S A 1995 Apr 11;92(8):3100-4 (UHM) kinase 1 (UHMK1) gene and schizophrenia on chromosome 1q23 3 Eur J Hum Genet Maucuer A, Le Caer JP, Manceau V, Sobel A. Specific Ser- Pro phosphorylation by the RNA-recognition motif Rajagopal C, Stone KL, Mains RE, Eipper BA. Secretion containing kinase KIS Eur J Biochem 2000 stimulates intramembrane proteolysis of a secretory granule Jul;267(14):4456-64 membrane enzyme J Biol Chem 2010 Nov 5;285(45):34632-42 Maucuer A, Ozon S, Manceau V, Gavet O, Lawler S, Curmi P, Sobel A. KIS is a protein kinase with an RNA recognition Zhang D, Tari AM, Akar U, Arun BK, LaFortune TA, Nieves- motif J Biol Chem 1997 Sep 12;272(37):23151-6 Alicea R, Hortobagyi GN, Ueno NT. Silencing kinase- interacting stathmin gene enhances erlotinib sensitivity by Pedraza N, Ortiz R, Cornadó A, Llobet A, Aldea M, Gallego inhibiting Ser p27 phosphorylation in epidermal growth C. KIS, a kinase associated with microtubule regulators, factor receptor-expressing breast cancer Mol Cancer Ther enhances translation of AMPA receptors and stimulates 2010 Nov;9(11):3090-9 dendritic spine remodeling J Neurosci 2014 Oct 15;34(42):13988-97 This article should be referenced as such: Petrovic V, Costa RH, Lau LF, Raychaudhuri P, Tyner AL. Arfelli, VC; Archangelo, LF. UHMK1 (U2AF FoxM1 regulates growth factor-induced expression of homology motif kinase 1). Atlas Genet Cytogenet kinase-interacting stathmin (KIS) to promote cell cycle progression J Biol Chem 2008 Jan 4;283(1):453-60 Oncol Haematol. 2018; 22(8):328-335. Puri V, McQuillin A, Datta S, Choudhury K, Pimm J, Thirumalai S, Krasucki R, Lawrence J, Quested D, Bass N, Crombie C, Fraser G, Walker N, Moorey H, Ray MK, Sule

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